scholarly journals Intestinal Barrier Dysfunction Exacerbates Neuroinflammation via the TLR4 Pathway in Mice With Heart Failure

2021 ◽  
Vol 12 ◽  
Author(s):  
Jun-Yu Huo ◽  
Wan-Ying Jiang ◽  
Ting Yin ◽  
Hai Xu ◽  
Yi-Ting Lyu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Intestinal Permeability ◽  
Intestinal Barrier ◽  
Sham Operation ◽  
Barrier Dysfunction ◽  
Intestinal Alkaline Phosphatase ◽  
Intestinal Barrier Dysfunction ◽  
Junction Protein ◽  
Elevated Expression ◽  
The Brain

AimsThe present study aimed to investigate alterations in neuroinflammation after heart failure (HF) and explore the potential mechanisms.MethodsMale wild-type (WT) and Toll-like receptor 4 (TLR4)-knockout (KO) mice were subjected to sham operation or ligation of the left anterior descending coronary artery to induce HF. 8 weeks later, cardiac functions were analyzed by echocardiography, and intestinal barrier functions were examined by measuring tight junction protein expression, intestinal permeability and plasma metabolite levels. Alterations in neuroinflammation in the brain were examined by measuring microglial activation, inflammatory cytokine levels and the proinflammatory signaling pathway. The intestinal barrier protector intestinal alkaline phosphatase (IAP) and intestinal homeostasis inhibitor L-phenylalanine (L-Phe) were used to examine the relationship between intestinal barrier dysfunction and neuroinflammation in mice with HF.ResultsEight weeks later, WT mice with HF displayed obvious increases in intestinal permeability and plasma lipopolysaccharide (LPS) levels, which were accompanied by elevated expression of TLR4 in the brain and enhanced neuroinflammation. Treatment with the intestinal barrier protector IAP significantly attenuated neuroinflammation after HF while effectively increasing plasma LPS levels. TLR4-KO mice showed significant improvements in HF-induced neuroinflammation, which was not markedly affected by intestinal barrier inhibitors or protectors.ConclusionHF could induce intestinal barrier dysfunction and increase gut-to-blood translocation of LPS, which could further promote neuroinflammation through the TLR4 pathway.

scholarly journals Asymptomatic Hyperamylasemia in Stevens-Johnson Syndrome Is Associated with Intestinal Barrier Dysfunction

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Yujen Tseng ◽  
Zhongguang Luo ◽  
Hongyang Zhang ◽  
Chengfeng Zhang ◽  
Jian Chen
Keyword(s):  
Serum Amylase ◽  
Intestinal Barrier ◽  
Stevens Johnson Syndrome ◽  
Fecal Occult Blood ◽  
Study Cohort ◽  
Barrier Dysfunction ◽  
Intestinal Barrier Dysfunction ◽  
Johnson Syndrome ◽  
Junction Protein ◽  
Clinical Awareness

Background/Objectives. Stevens-Johnson syndrome (SJS) is an allergic disease characterized by extensive epidermal detachment and mucositis. SJS involves both the skin and mucosal membranes, including the gastrointestinal tract. The present study is aimed at understanding the underlying reason of asymptomatic hyperamylasemia in patients with SJS, which may be associated with mucosal injury of the GI tract. Methods. A retrospective study on SJS patients was conducted at a tertiary medical center. All patients diagnosed as SJS, with available serum amylase index, were included. Clinical data of all subjects were retrospectively collected and analyzed. Colonic mucosal biopsies were obtained to measure tight junction protein expression. Results. A total of nine patients were included in the present study for study analysis. The average serum amylase of the study cohort was 228.78 ± 204.18   U / L . Among which, five patients had a positive fecal occult blood test (FOBT). Colonic mucosal biopsies were obtained and stained with occludin and zonula occludens-1 (ZO-1). The expression of occludin and ZO-1 was significantly downregulated in SJS patients ( p < 0.01 ), which was indicative of intestinal barrier dysfunction. Conclusion. Hyperamylasemia often extends beyond pancreatic diseases. Clinical awareness of asymptomatic hyperamylasemia secondary to other systemic diseases can help avoid unnecessary overexamination and overtreatment.

Abstract TP336: The Intestinal Barrier Dysfunction Induced by Intracerebral Hemorrhage Contributes to the Brain Edema

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Tian Wang ◽  
Bing Han ◽  
Yingjie Han ◽  
Ting Li ◽  
Fenghua Fu
Keyword(s):  
Intracerebral Hemorrhage ◽  
Brain Edema ◽  
Intestinal Permeability ◽  
Sham Group ◽  
Intestinal Barrier ◽  
Intestinal Injury ◽  
Brain Water Content ◽  
Barrier Dysfunction ◽  
The Brain ◽  
Brain Water

Background and Purpose: This study aims to investigate whether intracerebral hemorrhage (ICH) can lead to intestinal barrier dysfunction, and whether ICH-induced intestinal injury plays a role in brain edema. Methods: ICH mice model was prepared by an intrastriatal injection of bacterial collagenase. The following parameters were investigated at 3 h, 6 h, 12 h, 1 d, 2 d, 3 d, or 7 d after ICH preparation. Mice were given intragastrically with FITC-dextran and the intestinal permeability was evaluated by serum fluorescence measurement. Serum lipopolysaccharide (LPS) level was assayed with ELISA kits. Ileum and jejunum were stained with hematoxylin and eosin. Intestinal mucosal injuries were graded according to the scoring method (grade 0 to grade 4). Brain water content was evaluated via a wet/dry weight method. Correlations of intestinal injury, intestine permeability, LPS, and brain edema were analyzed using Pearson’s correlation analysis. Results: Compared with the Sham group, Ileum and jejunum damage occurred at 6 h after ICH, and the ICH-induced intestinal injury continued until 7 d. In line with the histopathological findings, the degree of ileum and jejunum injury was significantly increased at 6 h after ICH, showing mostly scores in Grade 1 to Grade 3 ( P < 0.05 or P < 0.01). After 6-h ICH, the intestinal permeability to FITC-dextran was higher compared to the Sham group, and the increase of intestinal permeability lasted 7 d ( P < 0.01). From 6 h to 7 d, serum LPS was significantly augmented ( P < 0.01). The brain content of the ipsilateral hemispheres was increased at 12 h, 1 d, 2 d, and 3 d after ICH ( P < 0.05 or P < 0.01), and the brain content of the contralateral hemispheres was also enhanced at 1 d, 2 d, and 3 d after ICH ( P < 0.01). The ileum and jejunum injury were positively associated with intestine permeability (r = 0.625, P < 0.01, r = 0.465, P < 0.01, respectively). The intestine permeability was positively associated with the serum level of LPS (r =0.585, P < 0.01). The LPS levels were positively associated with brain water content (r = 0.338, P < 0.01). Conclusion: ICH can cause intestinal mucosal injury. Consequently, the increase of intestinal permeability results in the translocation of endotoxins, which contributes to ICH-induced brain edema.

scholarly journals P011 Dysbiosis and Goblet cells depletion triggers early intestinal barrier dysfunction that precedes gut inflammation in IL-10 deficient mice (IL-10−/−)

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S135-S135 ◽  
Author(s):  
B López Cauce ◽  
M Puerto ◽  
J J García ◽  
J Miranda-Bautista ◽  
J Vaquero ◽  
...  
Keyword(s):  
Intestinal Permeability ◽  
Goblet Cell ◽  
Intestinal Barrier ◽  
Goblet Cells ◽  
Interleukin 10 ◽  
Length Ratio ◽  
Barrier Dysfunction ◽  
Gut Inflammation ◽  
Intestinal Barrier Dysfunction

Abstract Background Interleukin-10 deficient mouse (IL-10−/−) is a widely used model of spontaneous ileocolitis that resembles human inflammatory bowel disease (IBD); intestinal barrier dysfunction is an early pathophysiological event, but its underlying mechanisms are still unknown. The objective of this work is to study the natural history of ileocolitis in IL-10−/−, and unravel the influence of intestinal barrier dysfunction and dysbiosis in the development of overt inflammation. Methods Wild-type (WT) and IL-10−/− mice were followed until sacrifice at 3, 5, 10, 20, 57 and 70 weeks of life. Bodyweight, colonic weight/length ratio and in vivo intestinal permeability (measured by rectal administration of FITC-dextran) were registered. After the sacrifice, the colon was harvested and the evaluation of the expression of inflammatory (interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α), inducible nitric synthase (iNOS) and cyclooxygenase-2 (COX-2) and epithelial permeability (ZO-1, E-cadherin, Occludin, Claudins 2 and 7, and Reticulon-4B (RTN-4B) markers was performed by qPCR; expression of mucin-2 (MUC-2) and molecules involved in goblet cell maturation such as interleukin-18 (IL-18) and WAP Four-Disulphide Core Domain 2 (WFDC2), as well as the endoplasmic reticulum stress marker X-box-binding protein (Xbp)-1) by qPCR were also analysed. We also used colon slices for histologic evaluation with haematoxylin-eosin and alcian blue stainings. The microbiota composition was studied by sequencing of the V3-V4 regions of ribosomal 16S from faecal samples of all these mice. Results Compared with WT, IL-10−/− mice showed lower weight gain at all ages and a higher colonic weight/length ratio and histological evidence of inflammation at weeks 20 and 57. iNOS and IL-1b gene expression in the colon were significantly higher in IL-10−/− mice at weeks 10 and 20, respectively. Nevertheless, increased intestinal permeability was observed from week 10; the number of goblet cells and expression of MUC-2, IL-18, WFDC2 and XBP-1 were significantly lower in knockout mice from week 10. Moreover, dysbiosis in IL-10−/− mice began at week 5, increasing at 10 and showing the lowest diversity and appearance of pathogenic families at 20 weeks of age. Conclusion Dysbiosis and goblet cell depletion in the colon of IL-10−/− mice are associated with early intestinal barrier dysfunction, and precede overt gut inflammation in this animal model of IBD.

scholarly journals Intestinal barrier dysfunction as a therapeutic target for cardiovascular disease

2020 ◽  
Vol 319 (6) ◽  
pp. H1227-H1233
Author(s):  
Caitlin V. Lewis ◽  
W. Robert Taylor
Keyword(s):  
Heart Failure ◽  
Cardiovascular Disease ◽  
Intestinal Permeability ◽  
Gut Microbiome ◽  
Therapeutic Target ◽  
Barrier Function ◽  
Intestinal Barrier ◽  
Current Data ◽  
Intestinal Barrier Function ◽  
Barrier Dysfunction

The gut microbiome and intestinal dysfunction have emerged as potential contributors to the development of cardiovascular disease (CVD). Alterations in gut microbiome are well documented in hypertension, atherosclerosis, and heart failure and have been investigated as a therapeutic target. However, a perhaps underappreciated but related role for intestinal barrier function has become evident. Increased intestinal permeability is observed in patients and mouse models of CVD. This increased intestinal permeability can enhance systemic inflammation, alter gut immune function, and has been demonstrated as predictive of adverse cardiovascular outcomes. The goal of this review is to examine the evidence supporting a role for intestinal barrier function in cardiovascular disease and its prospect as a novel therapeutic target. We outline key studies that have investigated intestinal permeability in hypertension, coronary artery disease, atherosclerosis, heart failure, and myocardial infarction. We highlight the central mechanisms involved in the breakdown of barrier function and look at emerging evidence for restored barrier function as a contributor to promising treatment strategies such as short chain fatty acid, probiotic, and renin angiotensin system-targeted therapeutics. Recent studies of more selective targeting of the intestinal barrier to improve disease outcomes are also examined. We suggest that although current data supporting a contribution of intestinal permeability to CVD pathogenesis are largely associative, it appears to be a promising avenue for further investigation. Additional studies of the mechanisms of barrier restoration in CVD and testing of intestinal barrier-targeted compounds will be required to confirm their potential as a new class of CVD therapeutic.

scholarly journals Death following traumatic brain injury in Drosophila is associated with intestinal barrier dysfunction

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Rebeccah J Katzenberger ◽  
Stanislava Chtarbanova ◽  
Stacey A Rimkus ◽  
Julie A Fischer ◽  
Gulpreet Kaur ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Genome Wide Association Study ◽  
Intestinal Barrier ◽  
Nucleotide Polymorphisms ◽  
Barrier Dysfunction ◽  
Intestinal Barrier Dysfunction ◽  
Probability Of Death ◽  
Highly Correlated ◽  
The Brain

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Unfavorable TBI outcomes result from primary mechanical injuries to the brain and ensuing secondary non-mechanical injuries that are not limited to the brain. Our genome-wide association study of Drosophila melanogaster revealed that the probability of death following TBI is associated with single nucleotide polymorphisms in genes involved in tissue barrier function and glucose homeostasis. We found that TBI causes intestinal and blood–brain barrier dysfunction and that intestinal barrier dysfunction is highly correlated with the probability of death. Furthermore, we found that ingestion of glucose after a primary injury increases the probability of death through a secondary injury mechanism that exacerbates intestinal barrier dysfunction. Our results indicate that natural variation in the probability of death following TBI is due in part to genetic differences that affect intestinal barrier dysfunction.

scholarly journals Over-Expression of Intestinal Alkaline Phosphatase Attenuates Atherosclerosis

2021 ◽  
Author(s):  
Siddhartha S Ghosh ◽  
Jing Wang ◽  
Paul J Yannie ◽  
Remy C Cooper ◽  
Yashnoor K Sandhu ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Barrier Function ◽  
Intestinal Inflammation ◽  
Intestinal Barrier ◽  
Lipid Absorption ◽  
Apical Surface ◽  
Barrier Dysfunction ◽  
Intestinal Alkaline Phosphatase ◽  
Over Expression ◽  
Intestinal Barrier Dysfunction

Rationale: Intestinal Alkaline Phosphatase (IAP) is secreted by enterocytes and is present on the apical surface. It not only detoxifies bacterial endotoxin lipopolysaccharide (LPS) in the gut lumen and limits intestinal inflammation but also restricts translocation of LPS into systemic circulation. Diet-induced intestinal barrier dysfunction and subsequent development of metabolic endotoxemia seen in diabetes and heart disease is associated with reduced IAP levels. To examine the direct effects of increased IAP expression on barrier function and development of metabolic diseases, we developed intestine-specific IAP transgenic mice (IAP Tg ) over-expressing human chimeric IAP. Objective: The aim of this study was to evaluate the effects of intestine-specific IAP overexpression on Western-type diet (WD)-induced atherosclerosis in Ldlr -/- mice. Methods and Results: IAPTg mice crossed into Ldlr -/- background (Ldlr-/-IAP Tg ) and Ldlr -/- littermates were fed WD for 16 weeks. Intestinal barrier dysfunction was assessed by monitoring plasma LPS levels and histological examination of colon. Over-expression of IAP attenuated WD-induced disruption of the colonic mucous layer, reducing intestinal barrier dysfunction and plasma LPS levels. Significant reduction in body, liver and adipose tissue weight was also seen in WD-fed Ldlr -/- IAP Tg mice. Plasma and hepatic lipids were also significantly reduced in WD-fed Ldlr -/- IAP Tg mice. Consistently, intestinal lipid absorption was attenuated in Ldlr -/- IAP Tg mice with reduced expression of apical lipid transporters (CD36, FATP4 and NPC1L1) and intracellular lipid transport proteins (FABP1/2, SCP2). Attenuation of WD-induced atherosclerosis in Ldlr -/- IAP Tg mice was demonstrated by significant reduction in arch and total aortic lesions as seen by enface analyses as well as significantly reduced atherosclerotic lesions in the ascending aorta of these mice. Conclusions: IAP overexpression improves intestinal barrier function by maintaining the integrity of the mucin layer in WD fed Ldlr -/- IAPTg mice and attenuates intestinal lipid absorption. Thus, by limiting translocation of gut-derived LPS and/or reducing plasma lipids, over-expression of IAP attenuates development of WD-induced atherosclerosis.

scholarly journals Enterocyte-specific epidermal growth factor prevents barrier dysfunction and improves mortality in murine peritonitis

2009 ◽  
Vol 297 (3) ◽  
pp. G471-G479 ◽  
Author(s):  
Jessica A. Clark ◽  
Heng Gan ◽  
Alexandr J. Samocha ◽  
Amy C. Fox ◽  
Timothy G. Buchman ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Intestinal Permeability ◽  
Cecal Ligation ◽  
Intestinal Barrier ◽  
Protective Effects ◽  
Barrier Dysfunction ◽  
Intestinal Barrier Dysfunction ◽  
Septic Peritonitis ◽  
Epidermal Growth

Systemic administration of epidermal growth factor (EGF) decreases mortality in a murine model of septic peritonitis. Although EGF can have direct healing effects on the intestinal mucosa, it is unknown whether the benefits of systemic EGF in peritonitis are mediated through the intestine. Here, we demonstrate that enterocyte-specific overexpression of EGF is sufficient to prevent intestinal barrier dysfunction and improve survival in peritonitis. Transgenic FVB/N mice that overexpress EGF exclusively in enterocytes ( IFABP-EGF) and wild-type (WT) mice were subjected to either sham laparotomy or cecal ligation and puncture (CLP). Intestinal permeability, expression of the tight junction proteins claudins-1, -2, -3, -4, -5, -7, and -8, occludin, and zonula occludens-1; villus length; intestinal epithelial proliferation; and epithelial apoptosis were evaluated. A separate cohort of mice was followed for survival. Peritonitis induced a threefold increase in intestinal permeability in WT mice. This was associated with increased claudin-2 expression and a change in subcellular localization. Permeability decreased to basal levels in IFABP-EGF septic mice, and claudin-2 expression and localization were similar to those of sham animals. Claudin-4 expression was decreased following CLP but was not different between WT septic mice and IFABP-EGF septic mice. Peritonitis-induced decreases in villus length and proliferation and increases in apoptosis seen in WT septic mice did not occur in IFABP-EGF septic mice. IFABP-EGF mice had improved 7-day mortality compared with WT septic mice (6% vs. 64%). Since enterocyte-specific overexpression of EGF is sufficient to prevent peritonitis-induced intestinal barrier dysfunction and confers a survival advantage, the protective effects of systemic EGF in septic peritonitis appear to be mediated in an intestine-specific fashion.

scholarly journals A novel membrane protein Hoka regulates septate junction organization and stem cell homeostasis in the Drosophila gut

2020 ◽  
Author(s):  
Yasushi Izumi ◽  
Kyoko Furuse ◽  
Mikio Furuse
Keyword(s):  
Stem Cell ◽  
Membrane Protein ◽  
Intestinal Barrier ◽  
Septate Junction ◽  
Barrier Dysfunction ◽  
Septate Junctions ◽  
Cell Homeostasis ◽  
Intestinal Barrier Dysfunction ◽  
Epithelial Tumors ◽  
Junction Protein

AbstractSmooth septate junctions (sSJs) regulate the paracellular transport in the intestinal and renal system in arthropods. In Drosophila, the organization and physiological function of sSJs are regulated by at least three sSJ-specific membrane proteins: Ssk, Mesh, and Tsp2A. Here, we report a novel sSJ membrane protein Hoka, which has a single membrane-spanning segment with a short extracellular region having 13-amino acids, and a cytoplasmic region with three repeats of the Tyr-Thr-Pro-Ala motif. The larval midgut in hoka-mutants shows a defect in sSJ structure. Hoka forms a complex with Ssk, Mesh, and Tsp2A and is required for the correct localization of these proteins to sSJs. Knockdown of hoka in the adult midgut leads to intestinal barrier dysfunction, stem cell overproliferation, and epithelial tumors. In hoka-knockdown midguts, aPKC is up-regulated in the cytoplasm and the apical membrane of epithelial cells. The depletion of aPKC and yki in hoka-knockdown midguts results in reduced stem cell overproliferation. These findings indicate that Hoka cooperates with the sSJ-proteins Ssk, Mesh, and Tsp2A to organize sSJs, and is required for maintaining intestinal stem cell homeostasis through the regulation of aPKC and Yki activities in the Drosophila midgut.Summary statementDepletion of hoka, a gene encoding a novel septate junction protein, from the Drosophila midgut results in the disruption of septate junctions, intestinal barrier dysfunction, stem cell overproliferation, and epithelial tumors.

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